Dysfunctional TRIM31 of POMC Neurons Provokes Hypothalamic Injury and Peripheral Metabolic Disorder under Long-Term Fine Particulate Matter Exposure.

Particulate matter ≤2.5 µm (PM(2.5)) elevates risks of neurological and chronic metabolic diseases, but the underlying mechanisms linking PM(2.5)-induced central nervous system (CNS) injury to metabolic dysfunction remain unclear. Hypothalamic pro-opiomelanocortin-expressing (POMC+) neurons regulate systemic metabolic homeostasis, and tripartite motif-containing protein 31 (TRIM31) modulates inflammation and metabolism. Here, we investigated whether TRIM31 in POMC+ neurons mediates PM(2.5)-induced hypothalamic injury and peripheral metabolic disorders in mice subjected to 24-week PM(2.5) exposure. TRIM31 knockout in POMC(+) neurons (POMC(Cre/+;)TRIM31(flox/flox)) exacerbated PM(2.5)-;induced increases in mean blood pressure and fat weight, liver weight reduction, adipocyte hypertrophy, hepatic lipid deposition, energy expenditure abnormalities and insulin resistance. It also aggravated hypothalamic damage (downregulated NeuN, POMC and MC4R) and amplified neuroinflammation and oxidative stress. Conversely, AAV-mediated TRIM31 overexpression in POMC(+) neurons alleviated these pathological phenotypes. In vitro, TRIM31 deletion promoted reactive oxygen species (ROS) and inflammation in PM(2.5)-challenged hypothalamic neurons and microglia, while TRIM31 overexpression exerted opposite effects; microglial TRIM31 depletion exacerbated neuronal death via conditioned medium. Mechanistically, TRIM31 directly interacted with Nrf2, enhancing its K63-linked polyubiquitination and reducing K48-linked polyubiquitination to activate Nrf2 signaling, which was required for TRIM31-mediated attenuation of neuronal death and inflammation under PM2.5 stress. Collectively, our findings identify the TRIM31/Nrf2 axis as a key molecular switch governing POMC(+) neuronal loss, hypothalamic injury and consequent peripheral metabolic disorders triggered by long-term PM(2.5) exposure.